Varicella Zoster Virus CNS disease in hematopoietic cell transplantation: A single center experience

Background: Varciella Zoster Virus (VZV) can lead to serious complications in Hematopoietic Cell Transplant (HCT) recipients. Central nervous system (CNS) VZV can be one of the most devastating infections in transplant recipients, yet little is known about this rare disease. Objectives: To describe CNS VZV in the post-transplant period and to define potential risk factors in the HCT population. Methods: We reviewed the course of all patients who received a first HCT at the Fred Hutchinson Cancer Center (FHCRC) in Seattle, WA from 1/1996 through 12/2007. Data were collected retrospectively using the Long-Term Follow-Up database, which includes on-site examinations, outside records, laboratory tests, and yearly questionnaires. Patients were classified as CNS VZV if they had laboratory confirmation of VZV in the cerebrospinal fluid (CSF), or had zoster with associated clinical and laboratory findings consistent with CNS disease. Results: A total of six patients developed VZV CNS disease during the evaluation period (table 1). Diagnosis was confirmed in 3/6 by detection of VZV in CSF by PCR. All other patients had a clinical diagnosis based on the presence of CNS symptoms, zoster, lymphocytic pleiocytosis, and response to IV acyclovir. Patients who developed CNS disease had a mean age of 42 years (range 34-51) at time of transplant. CNS disease developed at a mean of 9 months posttransplantation (range 0.5-24 months), and severity varied, ranging from meningitis (3/6) to encephalitis/myelitis (3/6). All had active graft-versus host disease (GHVD) and all were being treated with immunosuppressive therapy at time of diagnosis. Fever and headache were the most common symptoms, but patients who developed focal CNS findings or seizures (3/6) had a more complicated clinical course. While most patients presented with classic VZV/zoster skin lesions, 2/6 patients had no dermatologic findings associated with their presentation. Four (66%) of patients who developed VZV CNS disease died, two related to VZV complications despite aggressive antiviral therapy. Conclusions: In this cohort of HCT patients, VZV CNS disease was a rare complication. Mortality due to CNS VZV is high, particularly in patients who develop focal neurologic findings or seizures. Even in the absence of skin lesions, VZV CNS disease should be considered in patients who develop fevers and neurologic symptoms.

Mise à jour sur l'hépatite E [An update on hepatitis E].

The hepatitis E virus (HEV) is an RNA virus transmitted via the fecal-oral route or through uncooked animal meat products. Of the 4 known genotypes, genotype 3 is responsible for autochthonous infections in industrialized countries, with a seroprevalence in Switzerland estimated as high as 22%. The majority of infections is asymptomatic but a minority of patients, notably men over 50 or with underlying liver disease, can present with severe acute hepatitis. Chronic hepatitis E with HEV of genotype 3 has been observed in immunosuppressed patients, mostly transplant recipients. Serology is not sufficiently sensitive, especially in immunosuppressed patients, making PCR identification the preferred test for diagnosing active infection. Ribavirin or interferon-alpha can be used to treat chronic hepatitis E if reduction of immunosuppressive treatment does not result in viral elimination.

Recommandations de vaccination pour les patients atteints de maladie chronique [Immunization guidelines regarding patients with a chronic disease].

Some chronic diseases--like renal failure, liver insufficiency, chronic lung disease, cardiac involvement, diabetes mellitus, asplenia--present limited defects of the immune system and/or a higher risk of infection; therefore, patients with such pathologies should get selective vaccinations. The efficacy of immunization decreases with disease progression; for this reason, these patients should be immunized as soon as possible. At the beginning of their disease, these patients do not need a specialized treatment and are followed by the general practitioner alone who is in charge of immunizing them as well as contact people of any immunocompromised patient. OFSP's regular vaccinations programme is recommended, as well as selective vaccinations against influenza, pneumococci and viral hepatitis, depending on the underlying chronic disease.

Mycosis fungoides in a lung transplant recipient with advanced ciclosporin nephropathy: management with mechlorethamine and subsequent renal transplantation.

Posttransplant cutaneous T cell lymphomas are rare and have been reported to have a poor prognosis. We report the case of a follicular mycosis fungoides in a lung transplant recipient who was successfully treated with topical mechlorethamine, prior to subsequent renal transplantation.

Lung cancer in the Swiss HIV Cohort Study: role of smoking, immunodeficiency and pulmonary infection.

BACKGROUND: Immunodeficiency and AIDS-related pulmonary infections have been suggested as independent causes of lung cancer among HIV-infected persons, in addition to smoking. METHODS: A total of 68 lung cancers were identified in the Swiss HIV Cohort Study (SHCS) or through linkage with Swiss Cancer Registries (1985-2010), and were individually matched to 337 controls by centre, gender, HIV-transmission category, age and calendar period. Odds ratios (ORs) were estimated by conditional logistic regression. RESULTS: Overall, 96.2% of lung cancers and 72.9% of controls were ever smokers, confirming the high prevalence of smoking and its strong association with lung cancer (OR for current vs never=14.4, 95% confidence interval (95% CI): 3.36-62.1). No significant associations were observed between CD4+ cell count and lung cancer, neither when measured within 1 year (OR for <200 vs ≥500=1.21, 95% CI: 0.49-2.96) nor further back in time, before lung cancer diagnosis. Combined antiretroviral therapy was not significantly associated with lung cancer (OR for ever vs never=0.67, 95% CI: 0.29-1.52), and nor was a history of AIDS with (OR=0.49, 95% CI: 0.19-1.28) or without (OR=0.53, 95% CI: 0.24-1.18) pulmonary involvement. CONCLUSION: Lung cancer in the SHCS does not seem to be clearly associated with immunodeficiency or AIDS-related pulmonary disease, but seems to be attributable to heavy smoking.

Valganciclovir to prevent or treat cytomegalovirus disease in organ transplantation.

Cytomegalovirus (CMV) is generally considered the most significant pathogen to infect patients following organ transplantation. Significant improvements have been achieved in the management of CMV disease over recent years, especially since the introduction of oral drugs such as oral ganciclovir followed by valganciclovir (VGC), a prodrug of ganciclovir with enhanced bioavailability. Several randomized controlled trials have shown that VGC is an efficacious and convenient oral drug to prevent or treat CMV disease in solid-organ transplant recipients. In this article, we discuss the clinical and pharmacological experience with the use of VGC for the management of CMV in solid-organ transplant recipients. Finally, novel strategies to further reduce the incidence of CMV disease after transplantation are also reviewed.

Influence of HIV-related immunodeficiency on the risk of hepatocellular carcinoma.

OBJECTIVE: To investigate HIV-related immunodeficiency as a risk factor for hepatocellular carcinoma (HCC) among persons infected with HIV, while controlling for the effect of frequent coinfection with hepatitis C and B viruses. DESIGN: A case-control study nested in the Swiss HIV Cohort Study. METHODS: Twenty-six HCC patients were identified in the Swiss HIV Cohort Study or through linkage with Swiss Cancer Registries, and were individually matched to 251 controls according to Swiss HIV Cohort Study centre, sex, HIV-transmission category, age and year at enrollment. Odds ratios and corresponding confidence intervals were estimated by conditional logistic regression. RESULTS: All HCC patients were positive for hepatitis B surface antigen or antibodies against hepatitis C virus. HCC patients included 14 injection drug users (three positive for hepatitis B surface antigen and 13 for antibodies against hepatitis C virus) and 12 men having sex with men/heterosexual/other (11 positive for hepatitis B surface antigen, three for antibodies against hepatitis C virus), revealing a strong relationship between HIV transmission route and hepatitis viral type. Latest CD4+ cell count [Odds ratio (OR) per 100 cells/mul decrease = 1.33, 95% confidence interval (CI) 1.06-1.68] and CD4+ cell count percentage (OR per 10% decrease = 1.65, 95% CI 1.01-2.71) were significantly associated with HCC. The effects of CD4+ cell count were concentrated among men having sex with men/heterosexual/other rather than injecting drug users. Highly active antiretroviral therapy use was not significantly associated with HCC risk (OR for ever versus never = 0.59, 95% confidence interval 0.18-1.91). CONCLUSION: Lower CD4+ cell counts increased the risk for HCC among persons infected with HIV, an effect that was particularly evident for hepatitis B virus-related HCC arising in non-injecting drug users.

Absence of BK viremia clearance after low-dose cidofovir therapy in kidney transplant recipients with BK virus associated nephropathy

Background: BK virus associated nephropathy occurs in 1-10% of kidney transplant recipients and may be a cause of graft loss. This infection is difficult to manage because of the absence of specific therapy. Cidofovir, a DNA polymerase inhibitor approved for the treatment of CMV retinitis, has shown in vitro activity against BK virus and some clinical efficacy when used at low-dose in uncontrolled series. Objective: To assess the efficacy of low-dose Cidofovir in the treatment of BK virus associated nephropathy. Method: Two adult kidney transplant recipients with biopsy-proven BK nephropathy and persistent high viremia (>10,000 copies/ml) despite 3-month reduction of immunosuppressive therapy were treated by Cidofovir 0.5 mg/kg fortnightly for a total of 16 weeks (8 doses). Clinical response was assessed by following BK viremia. Results: No decrease in BK viremia was observed at any point during cidofovir therapy (see figure). Creatinine clearance remained stable during therapy and no side-effects of Cidofovir were observed. Conclusions: Low-dose Cidofovir therapy was not associated with a clearance or with a significant decrease of BK viremia. This pilot study does not confirm previous reports suggesting clinical efficacy of Cidofovir for BK virus associated nephropathy.

One-year acyclovir prophylaxis for preventing varicella-zoster virus disease after hematopoietic cell transplantation: no evidence of rebound varicella-zoster virus disease after drug discontinuation.

No consensus exists on whether acyclovir prophylaxis should be given for varicella-zoster virus (VZV) prophylaxis after hematopoietic cell transplantation because of the concern of "rebound" VZV disease after discontinuation of prophylaxis. To determine whether rebound VZV disease is an important clinical problem and whether prolonging prophylaxis beyond 1 year is beneficial, we examined 3 sequential cohorts receiving acyclovir from day of transplantation until engraftment for prevention of herpes simplex virus reactivation (n = 932); acyclovir or valacyclovir 1 year (n = 1117); or acyclovir/valacyclovir for at least 1 year or longer if patients remained on immunosuppressive drugs (n = 586). In multivariable statistical models, prophylaxis given for 1 year significantly reduced VZV disease (P < .001) without evidence of rebound VZV disease. Continuation of prophylaxis beyond 1 year in allogeneic recipients who remained on immunosuppressive drugs led to a further reduction in VZV disease (P = .01) but VZV disease developed in 6.1% during the second year while receiving this strategy. In conclusion, acyclovir/valacyclovir prophylaxis given for 1 year led to a persistent benefit after drug discontinuation and no evidence of a rebound effect. To effectively prevent VZV disease in long-term hematopoietic cell transplantation survivors, additional approaches such as vaccination will probably be required.

No detectable indirect effects of late-onset Cytomegalovirus disease after valganciclovir (VGC) prophylaxis in kidney transplant recipients

Background: Cytomegalovirus (CMV) disease remains an important cause of morbidity after kidney transplantation and has been associated with acute rejection, graft loss and other indirect effects. A 3-month course of VGC prophylaxis reduces the incidence of CMV disease. However, little is known about the indirect effects of lateonset CMV disease after VGC prophylaxis. Objective: To evaluate the impact and indirect consequences of late-onset CMV disease after VGC prophylaxis in kidney transplant recipients. Methods: Retrospective analysis of 61 consecutive adult kidney transplant recipient with positive CMV serology (donor or recipient) who received VGC prophylaxis for 3 months and completed a follow-up of at least 2 years post-transplantation. Patients who developed CMV disease within 1 year after transplantation were compared to CMV disease-free patients for renal function (plasma creatinine values) at 1, 6, 12 and 24 months and for the incidence of graft loss, acute rejection, diabetes, cancer and opportunistic infections. Results: 8/61 (13%) patients developed CMV disease at a median of 131 days after transplantation (range: 98-220). The CMV incidence in D+/R- high risk patients was 6/18 (33%), while it was 2/43 (5%) in intermediate-risk patients (p < 0.01). All 8 patients were treated by oral valganciclovir (median 39 days; range: 19-119) with a complete resolution of CMV disease. As shown in the figure, there was no difference in creatinine values between the two groups at any time during follow-up. There was no graft loss, and the incidence of acute rejection, cancer and opportunistic infections did not differ between the two groups. The incidence of post-transplant diabetes was higher (38% vs 15%) in patients with CMV disease, but this difference was not significant (p = 0.4). Conclusions: An incidence of 13% of late-onset CMV disease was observed despite 3 months VGC prophylaxis. However, no indirect consequences were found. Moreover, therapy of CMV disease by oral VGC was effective and safe. Larger trials are needed to study whether late-onset CMV disease is associated with indirect consequences, as described with early-onset CMV.

HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies.

OBJECTIVE: To evaluate deaths from AIDS-defining malignancies (ADM) and non-AIDS-defining malignancies (nADM) in the D:A:D Study and to investigate the relationship between these deaths and immunodeficiency. DESIGN: Observational cohort study. METHODS: Patients (23 437) were followed prospectively for 104 921 person-years. We used Poisson regression models to identify factors independently associated with deaths from ADM and nADM. Analyses of factors associated with mortality due to nADM were repeated after excluding nADM known to be associated with a specific risk factor. RESULTS: Three hundred five patients died due to a malignancy, 298 prior to the cutoff for this analysis (ADM: n = 110; nADM: n = 188). The mortality rate due to ADM decreased from 20.1/1000 person-years of follow-up [95% confidence interval (CI) 14.4, 25.9] when the most recent CD4 cell count was <50 cells/microl to 0.1 (0.03, 0.3)/1000 person-years of follow-up when the CD4 cell count was more than 500 cells/microl; the mortality rate from nADM decreased from 6.0 (95% CI 3.3, 10.1) to 0.6 (0.4, 0.8) per 1000 person-years of follow-up between these two CD4 cell count strata. In multivariable regression analyses, a two-fold higher latest CD4 cell count was associated with a halving of the risk of ADM mortality. Other predictors of an increased risk of ADM mortality were homosexual risk group, older age, a previous (non-malignancy) AIDS diagnosis and earlier calendar years. Predictors of an increased risk of nADM mortality included lower CD4 cell count, older age, current/ex-smoking status, longer cumulative exposure to combination antiretroviral therapy, active hepatitis B infection and earlier calendar year. CONCLUSION: The severity of immunosuppression is predictive of death from both ADM and nADM in HIV-infected populations.

Docteur, j'ai un ganglion [Doctor, I have a lymph node]

To investigate a recently developed lymphadenopathy can be simple or complex. The medical history, presence or not of symptoms, the general physical examination, and the localization and characteristics of the adenopathy, most often lead to a diagnosis and therapy when indicated. Among young adults, the etiology is either infectious or reactive, rarely tumoral, as opposed to elderly persons. The most important step is to look at signs of severity (or non banality) such as an increased size, hard consistency, supra-clavicular location, an immunocompromised host, a history of Tb exposition. If present, these signs will trigger a biopsy with cyto- or histopathological examination mostly to rule out a malignant tumor. This article reviews the practical steps of an investigation of an isolated adenopathy in an adult patient.

European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients: summary of the ECIL 3--2009 update.

In 2005, several groups, including the European Group for Blood and Marrow Transplantation, the European Organization for Treatment and Research of Cancer, the European Leukemia Net and the Immunocompromised Host Society created the European Conference on Infections in Leukemia (ECIL). The main goal of ECIL is to elaborate guidelines, or recommendations, for the management of infections in leukemia and stem cell transplant patients. The first sets of ECIL slides about the management of invasive fungal disease were made available on the web in 2006 and the papers were published in 2007. The third meeting of the group (ECIL 3) was held in September 2009 and the group updated its previous recommendations. The goal of this paper is to summarize the new proposals from ECIL 3, based on the results of studies published after the ECIL 2 meeting: (1) the prophylactic recommendations for hematopoietic stem cell transplant recipients were formulated differently, by splitting the neutropenic and the GVHD phases and taking into account recent data on voriconazole; (2) micafungin was introduced as an alternative drug for empirical antifungal therapy; (3) although several studies were published on preemptive antifungal approaches in neutropenic patients, the group decided not to propose any recommendation, as the only randomized study comparing an empirical versus a preemptive approach showed a significant excess of fungal disease in the preemptive group.